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Title: New directions towards the synthesis of bicyclo[1.1.1]pentane derivatives
Author: Caputo, Dimitri
ISNI:       0000 0004 7966 2495
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Bicyclo[1.1.1]pentanes have emerged as bioisosteres, used by medicinal chemists to replace 1,4-disubstituted arenes and improve the physicochemical properties of the drugs they synthesise. The existing methods to synthesise 1,3-disubstituted bicyclo- [1.1.1]pentane involve toxic reagents, hazardous chemistries and lengthy synthetic sequences. We present in this thesis a novel, modular way to access 1,3-disubstituted bicyclo[1.1.1]pentane as well as monosubstituted bicyclo[1.1.1]pentane (Figure 1). The first chapter presents a triethylborane-initiated atom transfer radical addition reaction of organohalides on tricyclo[,3]pentane (1) to access in a rapid and efficient manner brominated and iodinated bicyclo[1.1.1]pentane (2). The reduction of the C-I bond of iodinated bicyclo[1.1.1]pentanes is presented in the second chapter. Tris(trimethylsilyl)silane was used as the reducing agent and triethylborane as the initiator, providing a less toxic alternative to tin hydride reductions and affording monosubstituted bicyclo[1.1.1]pentanes building blocks such as acids, amides, amines and amino acids (3). Nucleotides, peptides and drugs were successfully labelled with a bicyclo[1.1.1]pentane unit. The third chapter focusses on an iron-catalysed Kumada-Tamao-Corriu cross-coupling reaction of iodinated bicyclo[1.1.1]pentane to form arylated bicyclo[1.1.1]pentane (4). The reaction is particularly efficient with electron-rich organomagnesium reagents. A analogue to the drug Flurbiprofen was synthesised in excellent yield in just two steps from ethyl 2-iodopropionate and 1.
Supervisor: Anderson, Edward A. Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available